Identification of Temporal and Region-Specific Myocardial Gene Expression Patterns in Response to Infarction in Swine

Abstract

Molecular mechanisms associated with pathophysiological changes in ventricular remodelling due to myocardial infarction (MI) remain poorly understood. We analyzed changes in gene expression by microarray technology in porcine myocardial tissue at 1, 4, and 6 weeks post-MI.MI was induced by coronary artery ligation in 9 female pigs (30–40 kg). Animals were randomly sacrificed at 1, 4, or 6 weeks post-MI (n = 3 per group) and 3 healthy animals were also included as control group. Total RNA from myocardial samples was hybridized to GeneChip® Porcine Genome Arrays. Functional analysis was obtained with the Ingenuity Pathway Analysis (IPA) online tool. Validation of microarray data was performed by quantitative real-time PCR (qRT-PCR).More than 8,000 different probe sets showed altered expression in the remodelling myocardium at 1, 4, or 6 weeks post-MI. Ninety-seven percent of altered transcripts were detected in the infarct core and 255 probe sets were differentially expressed in the remote myocardium. Functional analysis revealed 28 genes de-regulated in the remote myocardial region in at least one of the three temporal analyzed stages, including genes associated with heart failure (HF), systemic sclerosis and coronary artery disease. In the infarct core tissue, eight major time-dependent gene expression patterns were recognized among 4,221 probe sets commonly altered over time. Altered gene expression of ACVR2B, BID, BMP2, BMPR1A, LMNA, NFKBIA, SMAD1, TGFB3, TNFRSF1A, and TP53 were further validated.The clustering of similar expression patterns for gene products with related function revealed molecular footprints, some of them described for the first time, which elucidate changes in biological processes at different stages after MI.

UM206, a selective Frizzled antagonist, attenuates adverse remodeling after myocardial infarction in swine

“…Wnt3a was upregulated in the infarcted myocardium in the present study but downregulated in this previous study at 3 weeks after MI, 28 whereas unchanged at 6 weeks after MI. 28 Also, downstream targets in the Wnt/Fzd signaling cascade were similarly affected by MI; Axin2 was decreased, whereas APC was unaltered. 28 UM206 treatment reduced the upregulation of Wnt3a in the infarcted tissue.…”

“…Most of our findings regarding changes in activation of Wnt/Fzd signaling are in accordance with a recently published study in swine in which gene expression was evaluated using microarrays. 28 Thus, Fzd2 was increased, whereas Fzd4 was decreased in infarcted myocardium as compared with remote myocardium. Wnt3a was upregulated in the infarcted myocardium in the present study but downregulated in this previous study at 3 weeks after MI, 28 whereas unchanged at 6 weeks after MI.…”

“…28 Thus, Fzd2 was increased, whereas Fzd4 was decreased in infarcted myocardium as compared with remote myocardium. Wnt3a was upregulated in the infarcted myocardium in the present study but downregulated in this previous study at 3 weeks after MI, 28 whereas unchanged at 6 weeks after MI. 28 Also, downstream targets in the Wnt/Fzd signaling cascade were similarly affected by MI; Axin2 was decreased, whereas APC was unaltered.…”

Three-Dimensional and Biomimetic Technology in Cardiac Injury After Myocardial Infarction: Effect of Acellular Devices on Ventricular Function and Cardiac Remodelling

“…These membranes illed with a self-assembling peptide hydrogel and cell with cardiac potential were fully vascularized with functional vessel and observed via echocardiography positive efects on global cardiac motility [42]. The results suggested, in this case, that the beneits of biodegradable scafolds were not only due to local reduction in scar size, but to a more general event [43,44]. Recent experimental studies have failed to answer important aspects of cell therapy.…”

MicroRNAs in myocardial ischemia: identifying new targets and tools for treating heart disease. New frontiers for miR-medicine

“…A number of transcriptome studies have been applied to CvD, with the aim of improving diagnosis, prognosis, and therapeutic assessment [5][6][7]. Myocardial biopsies of patients suffering from acute/chronic myocardial ischemia, as well as animal models of ischemia and reperfusion (I/R), have revealed changes in gene expression which seem to be specific for the cardiac ischemic injury [8][9][10]. MicroRNAs (miRNAs) are important regulators of gene expression, constituting a major area of investigation in cardiovascular research [11].…”